Easy lactamization of Gln(Asn)--Pro--NH 2 with the formation of cyclic dipeptides with the dikctopiperazine structure (mimetics of the cortformational fragments of linear tripeptides with the X--Pro trans-bond) was observed in the synthesis of tripeptide GIp--GIn--Pro--NH 2 modified by the replacement of histidine with obligatory similar glutamine in thyroliberin (GIp--His--Pro--NH 2, TRH) and in the synthesis of its structural analog [Asn2]TRH. Ion peaks corresponding to the Glp and Pro amino acid residues were revealed in the mass spectra of the peptides synthesized. The biological properties of the compounds obtained were determined indicating that the obligatory replacement resulted in an increased physiological specificity of [GIn2ITRH. The enhanced activity of conformationally restricted cyclic peptides compared to linear ones suggests that the biologically active conformation responsible for the antidepressant activity of linear TRH analogs is the conformation with X--Pro transbond.Key words: thyroliberin, structural modification, obligatory replacement; glutaminyl(asparaginyl)prolylarnide, tactamization; cyclodipeptides, antidepressant activity, biologically active conformation.The use of natural peptides in medicine is associated with several difficulties due to such disadvantages as fast metabolism, restricted penetration into brain, and biological multifunetionality. Therefore, the majority of commercially available drugs of peptide nature are modified analogs of natural peptides.The results of clinical and pharmacological studies indicate that the action of the natural hormone thyroliberin Glp--His--Pro--NH 2 (TRH) on the central nervous system is multi functional, i,2 To study the possibility of narrowing the spectrum of neurotropic activity of TRH, we modified its structure and studied the influence of the latter on the biological activity of the analogs obtained. 3-5 In this work, of numerous different variants of modification of natural peptides, we used the method proposed previously: replacement of obligatory similar amino acids in peptide. 6,7 Therefore, histidine in thyroliberin was replaced by obligatory, similar glutamine and asparagine structurally similar to the latter.The condensation of prolylamide with p-nitrophenyl N-tert-butyloxycarbonylglutaminate in the presence of N-hydroxybenzotriazole (HOBt) gave dipeptide, which after acidolytic deprotection reacted with pentafluorophenyl pyroglutaminate (Scheme 1, n = 2). In addition to the pyroglutaminylprolylamide (1) expected, the reaction mixture contained 3-(l,4-dioxooctahydropyrrolo[ 1,2-a]pyrazin-3-yl)propanamide (2) and pyroglutamylprolylamide (3), whose compositions and structures indicate that their formation is most likely related to intramolecular cyelization ofglutaminylprolylamide after deprotonation of its primary amino group (Scheme 2).It can be assumed that mild conditions of secondary reactions forming diketopiperazine (2) and pyrrolidone (3) structures are the result of the intramolecular activation of carboxamide groups of g...
